The Fructose Epidemic

By Robert H. Lustig, MD

ABSTRACT Fructose consumption (as both high fructose corn syrup and sucrose) has increased coincidentally with the

worldwide epidemics of obesity and metabolic syndrome.

Fructose is a primary contributor to human disease as it

is metabolized in the liver differently to glucose, and is

more akin to that of ethanol. When consumed in large

amounts, fructose promotes the same dose-dependent

toxic effects as ethanol, promoting hypertension, hepatic

and skeletal muscle insulin resistance, dyslipidemia and

fatty liver disease. Also similar to ethanol, through direct

stimulation of the central nervous system “hedonic

pathway” and indirect stimulation of the “starvation pathway,”

fructose induces alterations in central nervous system

energy signaling that lead to a vicious cycle of excessive

consumption, with resultant morbidity and mortality.

Fructose from any source should be regarded as

“alcohol without the buzz.” Obesity prevention

and treatment is ineffective in the

face of the current “fructose glut”

in our food supply. We must learn

from our experiences with ethanol

and nicotine that regulation of

the food industry, along with individual

and societal education,

will be necessary to combat this

fructose epidemic.

INTRODUCTION

As America’s (and the world’s)

collective girth continues to increase,

we ponder the answer to our

dilemma: Who or what are to blame

for the obesity epidemic? That depends

upon who you ask. The Institute of Medicine says

it is an interaction between genetics and environment.

Well, our genetics have not changed in 30 years but our

environment sure has, and in particular, our diet. The distribution

curve for Body Mass Index (BMI) shows that all

segments of the population are increasing in weight (1),

so whatever is happening is clearly pervasive and insidious.

Even developing countries that have adopted a Western

diet for convenience and expense have paid for it by

manifesting the same obesity prevalence, co-morbidity

profi les and mortality (2).

SECULAR TRENDS IN FRUCTOSE

CONSUMPTION

One of the striking features of the modern Western diet

is its reliance on refi ned carbohydrate as the predominant

energy source. Due to the “low-fat” admonition by

the United States Department of Agriculture (USDA),

American Medical Association and American Heart Association

(AHA) in the early 1980’s, the percentage of fat

in the Western diet has reduced from 40% to 30% over

the past 25 years; which has resulted in the percentage of

carbohydrate rising from 40% to 55%; coinciding with

the obesity epidemic. Of this, a sizeable and

ever-increasing portion of the diet is attributable

to monosaccharides and disaccharides

used to sweeten foods

and drinks. Furthermore, in response

to the market for lower

fat fare, food companies have

chosen to substitute disaccharides

to maintain palatability of

processed foods. Until recently

the most commonly used sugar

in the U.S. diet was disaccharide

sucrose (e.g. cane or beet

sugar) which is composed of 50%

fructose and 50% glucose. However,

in North America and many other

countries, due to its abundance, sweetness,

and low price, high-fructose corn syrup

(HFCS) which contains between 42% and 55% of the

monosaccharide fructose, has overtaken sucrose as the

most ubiquitous caloric sweetener. These factors have led

to an inexorable rise in fructose consumption. Prior to

1900, Americans consumed approximately 15 gm/day of

fructose, mainly through fruits and vegetables. Prior to

World War II this amount had increased to 24 gm/day. By

THE BARIATRICIAN • 11

1977 fructose intake was 37 gm/day; by 1994 55 gm/day;

and currently Vos et al. estimates that adolescents average

72.8 gm/day (3). Thus current fructose consumption

has incrementally increased 5-fold compared to a century

ago. Disappearance data over the past 25 years from Economic

Research Service (ERS) of the USDA also supports

this secular trend. The ERS documents partial substitution

for sucrose by HFCS; however annual per capita

total caloric sweetener usage has increased from 73 to 95

lbs in that interval. Although soda has received most of

the attention (4, 5), high fruit juice intake (sucrose) is also

associated with childhood obesity, especially by lower income

families (6), although it is not captured in the ERS.

Thus, after adjustment for juice intake, per capita consumption

of mono- and disaccharides is at approximately

113 lbs/yr or 1/3 lb/day for all Americans.

HOW WE GOT HERE: POLITICAL,

ECONOMIC, AND MEDICAL DRIVERS

OF FRUCTOSE CONSUMPTION

The reader is referred to The Omnivore’s Dilemma (7)

for a complete discussion of the political and economic

factors that led to the secular trend in fructose consumption.

In brief, the 1966 industrialization of the discovery

of the glucose oxidase process to convert glucose to fructose

(8), combined with a directed policy by the

USDA in the 1970’s to reduce the price of food

by advancing growth and production of corn as

a dietary staple, provided the political and economic

impetus for this trend. In addition, during

this decade the medical establishment focused

on dietary reduction of coronary heart disease.

Two competing schools of thought dominated

this discussion. John Yudkin, a British physiologist

and nutritionist, championed the anti-sugar

movement. His work “Pure, White, and Deadly”

(9) espoused the primary role of sugar in human

disease. Conversely, the anti-saturated fat

movement was spearheaded by Minnesota epidemiologist

Ancel Keys. His work, the Seven

Countries: study (10), was one of the fi rst multivariate

linear regression analyses. A review

of this document (P. 262) notes: “The fact that

the incidence of coronary heart disease was signifi

cantly correlated with the average percentage

of calories from sucrose in the diets is explained

by the intercorrelation of sucrose with saturated

fat. Partial correlation analysis demonstrates that

with saturated fat constant there was no signifi -

cant correlation between dietary sucrose and the incidence

of coronary heart disease” (10). However, Keys neglected

to perform the converse analysis demonstrating that the

effect of saturated fat on cardiovascular disease (CVD)

was independent of sucrose. In other words, sucrose and

saturated fat co-migrated; it is impossible to tease out the

relative contributions of sucrose vs. saturated fat on CVD

from this study.

Furthermore, the medical establishment based their

low-fat recommendations on the goal of LDL reduction;

however, several studies have since demonstrated little to

no effect of low-fat diets on weight gain or CVD events

(11, 12). However, we now know that there are two LDL’s.

The large buoyant or Type A LDL is driven by dietary fat,

but is neutral from a cardiovascular standpoint. The small

dense or Type B LDL, which is driven by carbohydrate

and fructose (13), is the species associated with CVD (14).

Conversely, we have ample evidence that triglyceride

(TG) is a major risk factor for CVD (15) and that fructose

consumption is a primary contributor to TG accumulation

(16, 17). A recent analysis has led the AHA Nutrition

Committee to publish a policy statement on the negative

role of sugars in the pathogenesis of CVD (18).

Figure 1: Effects of introduction of corn sweeteners (HFCS) to

the American diet in 1975 on: a) the U.S. Producer Price Index

for sugar; b) the U.S. and international (London) price of

sugar; and c) the U.S. retail price of sugar and on HFCS. Data

document stabilization or lowering of sugar prices.

12 • THE BARIATRICIAN

HIGH FRUCTOSE CORN SYRUP (HFCS)

VS. SUCROSE

Although many consumer activist groups have specifi -

cally vilifi ed HFCS as the cause of obesity and CVD, scientifi

c studies of acute satiety vs. energy intake support

the notion that HFCS is not metabolically different from

sucrose (19-27). This has led to a vociferous campaign by

the Corn Refi ners Association to infl uence the debate on

fructose consumption by equating HFCS with sucrose,

suggesting that it is no different, “natural,” and it is safe

(see www.sweetsurprise.com). Indeed, the distinction between

HFCS and sucrose is not metabolic (as they are

essentially equivalent), but rather economic. The introduction

of HFCS to the Western diet in 1975 resulted in

stability of the U.S. Producer Price Index for sugar, and

sizeable reductions in the U.S. and international price of

sugar (Fig. 1). HFCS on average costs about one third

that of sucrose. This, along with changes in the Farm Bill

and food policy, promoted the addition of fructose to our

collective diets; not just in soft drinks and juice, but in

salad dressing, condiments, baked goods and virtually

every processed food, which raised our total consumption

5-fold in the last 100 years. Below, it becomes clear that it

is not the specifi c vehicle (sucrose vs. HFCS) that makes

it unsafe, but rather the total dose of fructose.

CORRELATION OF FRUCTOSE CONSUMPTION

WITH DISEASE

Numerous reviews have indirectly implicated fructose

consumption in the current epidemics of obesity and

Type 2 Diabetes Mellitus (T2DM) (28-30). Correlative

studies in humans link soft drink consumption with energy

overconsumption, body weight, poor nutrition (31)

and T2DM (32). Similarly, juice consumption also correlates

with risk for T2DM (33), suggesting that excessive

fructose consumption is playing a role in the epidemics

of insulin resistance, obesity, hypertension, dyslipidemia,

and T2DM in humans (28, 34-38). Collectively, this constellation

of fi ndings is referred to as the Metabolic Syndrome

(MetS). Conversely, early short-term prospective

studies limiting soft drink ingestion in children have met

with some success in stabilization of weight and CVD

parameters (39, 40).

MECHANISMS OF FRUCTOSE

TOXICITY

Although others have already pointed out the unique

metabolic effects of fructose (28-30, 34, 36, 38), this review

was written to outline the unique, pernicious, and

dose-dependent toxic effects of fructose in the pathogenesis

of both metabolic disease and excessive consumption.

Fructose is similar in its metabolism to a more familiar

toxin, ethanol. Therefore, it is necessary to delineate the

hepatic outcomes of metabolism of glucose and ethanol

fi rst. In each case, we will follow a 120 kcal oral bolus of

each carbohydrate.

Hepatic Glucose Metabolism

Glucose is the body’s preferred carbohydrate substrate

for energy metabolism. Each cell in the body can utilize

glucose for energy. Upon ingestion of 120 kcal of glucose

(e.g. two slices of white bread) (Fig. 2a), 24 kcal

(20%) enter the liver; the remaining 96 kcal (80%) of the

glucose bolus are utilized by other organs (41). Plasma

glucose levels rise, insulin is released by the pancreas

which binds to its receptor on the liver, generating two

metabolic signals (42). The fi rst is the phosphorylation of

the forkhead protein Foxo1; which reduces the expression

of the enzymes of gluconeogenesis (GNG), to keep blood

sugar levels from rising (43). The second is an increase

in the expression of the transcription factor Akt, which

causes the majority of G6P (about 20 kcal) to be deposited

as the non-toxic storage carbohydrate glycogen. Only a

small amount of G6P is broken down by the Embden-

Meyerhoff glycolytic pathway to pyruvate (approx 4 kcal).

Pyruvate enters the mitochondria where it is converted

to acetyl-CoA, which then participates in the Krebs tricarboxylic

acid (TCA) cycle, which generates adenosine

triphosphate (ATP), the chemical storage form of energy,

and carbon dioxide. Any pyruvate not metabolized in the

Figure 2: Hepatic metabolism of 120 kcal carbohydrate:

a) glucose; b) ethanol; and c) sucrose (fructose).

Similarities in hepatic metabolism between

ethanol and fructose are highlighted.

THE BARIATRICIAN • 13

mitochondrial TCA cycle exits back into the cytoplasm

as citrate through the “citrate shuttle” (44). This small

amount of citrate (perhaps 0.5 kcal) can serve as substrate

for the process of de novo lipogenesis, which turns excess

citrate into free fatty acids (FFA). These can then be

packaged with apolipoprotein B (apoB) to form very low

density lipoproteins (VLDL; measured in the triglyceride

fraction), which are transported out of the liver, and can

serve as a substrate for atherogenesis or obesity. Thus,

in response to a 120 kcal glucose bolus, only a tiny fraction

(less than 1 kcal) contributes to adverse metabolic

outcomes.

Hepatic Ethanol Metabolism

Ethanol is a naturally occurring carbohydrate, but is

also recognized as both an acute central nervous system

(CNS) toxin and chronic hepatotoxin, due to its unique

dose-dependent hepatic metabolism (Fig. 2b). Upon ingestion

of 120 kcal of ethanol (e.g. 1.5 oz. of 80 Proof

hard spirits), approximately 10% (12 kcal) is metabolized

within the stomach and intestine as a fi rst-pass effect, and

10% is metabolized by the brain and other organs (41).

Thus approximately 96 calories reach the hepatocyte (4

times more than with glucose). Ethanol enters the liver

and is converted by alcohol dehydrogenase 1B to form the

toxic substrate acetaldehyde, which in high dosage can

promote free radical formation and toxic damage. Acetaldehyde

is then quickly metabolized by the enzyme aldehyde

dehydrogenase 2 to acetic acid, which can then enter

the mitochondrial TCA cycle (as per glucose, above); but

now, a large amount of excess citrate is formed (perhaps

70 kcal), which exits into the cytosol and then participates

in synthesis of fatty acids through de novo lipogenesis.

Thus, the metabolism of an ethanol bolus is likely

to cause the liver to increase FFA and VLDL production,

and contribute to dyslipidemia. Intrahepatic lipid and

ethanol are both able to induce the transcription of the

enzyme c-jun N-terminal kinase-1 (JNK-1) (45). This enzyme

is the bridge between hepatic energy metabolism

and infl ammation; and once induced, begins the infl ammatory

cascade (46). As part of its infl ammatory action,

JNK-1 activation induces serine phosphorylation of insulin

receptor substrate-1 (IRS-1) in the liver (47), leading

to hepatic insulin resistance, hepatic triglyceride accumulation

in lipid droplets, with resultant infl ammation (48);

eventually leading to alcoholic steatohepatitis, and ultimately

to cirrhosis. Lastly, FFA can exit the liver, which

can contribute to skeletal muscle insulin resistance. The

VLDL produced (perhaps 30 kcal) can be transported to

the adipocyte to serve as a substrate for obesity, or participate

in atherogenic plaque formation. Thus, in response

to a 120 kcal ethanol bolus, a large fraction (perhaps 40

kcal) can contribute to disease.

Hepatic Fructose Metabolism and the MetS

The liver is the only organ possessing the Glut5 fructose

transporter and is solely responsible for fructose metabolism

(49). Upon ingestion of 120 kcal of sucrose (e.g.

8 oz. of orange juice; composed of 60 kcal glucose and 60

kcal fructose) (Fig. 2c), the entire 60 kcal fructose bolus

reaches the liver, along with 20% of the glucose bolus

(12 kcal), for a total of 72 kcal; in other words, the liver

must handle triple the substrate as it did for glucose alone

Figure 2: Hepatic metabolism of 120 kcal carbohydrate:

a) glucose; b) ethanol; and c) sucrose (fructose).

Similarities in hepatic metabolism between

ethanol and fructose are highlighted.

Figure 2: Hepatic metabolism of 120 kcal carbohydrate:

a) glucose; b) ethanol; and c) sucrose (fructose).

Similarities in hepatic metabolism between

ethanol and fructose are highlighted.

14 • THE BARIATRICIAN

(50). The fructose is immediately converted to fructose-1-

phosphate (F1P) by the enzyme fructokinase (51), depleting

the hepatocyte of intracellular phosphate. This leads

to activation of the enzyme adenosine monophosphate

(AMP) deaminase-1, which converts the adenosine phosphate

breakdown products into the cellular waste product

uric acid (52, 53). Buildup of urate in the circulation inhibits

endothelial nitric oxide synthase (eNOS), resulting

in decreased nitric oxide (NO) and contributing to hypertension

(54-56). Almost the entire F1P load (50 kcal) is

metabolized directly to pyruvate, entering the mitochondrial

TCA cycle; again, excess citrate (perhaps 40 kcal)

will be exported to the cytosol, to participate in de

novo lipogenesis, with resultant dyslipidemia from

FFA and VLDL formation. Alternatively, a proportion

(10 kcal) of early glycolytic intermediaries

will recombine to form fructose-1,6-bisphosphate,

which then also combines with glyceraldehyde to

form xylulose-5-phosphate (X5P) (57, 58), which

activates carbohydrate response element binding

protein (ChREBP), also stimulating de novo lipogenesis

and contributing to fructose-induced dyslipidemia

(13, 17, 59-62). FFA export from the liver

leads to uptake into skeletal muscle, resulting in

skeletal muscle insulin resistance (63, 64). Some of

the FFA will precipitate in the hepatocyte, leading

to lipid droplet accumulation (65). Intrahepatic lipid

and FIP are both able to induce the transcription of

JNK-1 (45), which induces serine phosphorylation

of insulin receptor substrate-1 (IRS-1) in the liver

(47), thereby preventing normal insulin-stimulated

tyrosine phosphorylation of IRS-1, and promoting hepatic

insulin resistance. This will prevent Foxo1 from becoming

phosphorylated; Foxo1 enters the nucleus and gluconeogenesis

ensues, raising blood sugar and furthering the

hyperinsulinemia (43). Thus, in response to a 120 kcal

sucrose bolus, a large fraction (perhaps 40 kcal) can contribute

to disease.

Comparison of Hepatic Metabolic Detriments of Fructose

vs. Ethanol

As the brain does not possess the Glut5 transporter,

fructose does not lead to the acute CNS toxic effects like

those of ethanol. However, its hepatic metabolic profi le

strongly resembles that of ethanol. Table 1 demonstrates

the hepatic burden of a can of beer vs. a can of soda. Both

contain 150 kcal per 12 oz. can. The fi rst pass effect of

ethanol in the stomach and intestine removes 10% of the

ethanol. In the case of beer (3.6% ethanol and 6.6% other

carbohydrate (e.g. maltose, which is a glucose disaccharide),

this amounts to 92 calories reaching the liver, while

for soda this amounts to 90 calories reaching the liver.

Thus, hepatic metabolism of either fructose or ethanol results

in the majority of energy substrate being converted

to lipid, without any insulin regulation or ability to be

diverted to non-toxic intermediaries such as glycogen.

Intrahepatic lipid generation promotes infl ammation and

insulin resistance (66). Indeed, the hepatic metabolic

strain of beer and soda are congruous; such that beer or

sugar sweetened beverage consumption similarly led to

visceral adiposity, insulin resistance, and the metabolic

syndrome.

FRUCTOSE EFFECTS ON THE CNS LEAD

TO EXCESSIVE CONSUMPTION

The limbic structures central to the hedonic pathway

that motivates the “reward” of food intake are the ventral

tegmental area (VTA) and nucleus accumbens (NA). The

NA is also referred to as the “pleasure center” of the brain

(67) and is the seat of goal-oriented behavior. This is also

the brain area responsive to nicotine, morphine, cannabinoids,

amphetamine, nicotine, and ethanol (68). Food intake

is a result of activation of the reward pathway; for

example, administration of morphine to the NA increases

food intake in a dose-dependent fashion (69). Dopamine

neurotransmission from the VTA to the NA mediate the

reward properties of food (70). Leptin and insulin receptors

are co-localized in VTA neurons (71), and both

hormones have been implicated in modulating rewarding

responses to food and other pleasurable stimuli. Leptin

decreases VTA-NA activity, and extinguishes reward for

food (72, 73).

Soda (12 oz can) Beer (12 oz can)

Calories 150 150

Percent Carbohydrate 10.5% (sucrose) 3.6% (alcohol)

5.3% (other

carbs)

Calories From:

Fructose 75 (4.1 kcal/gm)

Alcohol 90 (7 kcal/gm)

Other carbs 75 (glucose) 60 (maltose)

1st pass stomachintestine

metabolism

Calories Reaching

Liver

90 92

Table 1: Similarities between soda and beer with respect

to hepatic handling

THE BARIATRICIAN • 15

However, increasing the palatability of food by addition

of fructose undermines normal satiety signals, and

as a result increases total caloric consumption both in

direct and indirect ways. Direct effects of fructose include

motivation of food intake independent of energy

need (74-79). Indeed, in animal models, sugar consumption

can lead to dependence (80). There are four indirect

effects of fructose on excessive food consumption. First,

fructose does not stimulate a leptin rise, thus contributing

acutely to a diminished sense of satiety (81). Secondly,

fructose induces hypertriglyceridemia, which reduces

leptin transport across the blood-brain barrier (82). The

third is chronic hyperinsulinemia, which interferes with

leptin signal transduction at the second messenger level

(83). By reducing leptin’s ability to extinguish hunger at

the hypothalamus, and likely leptin’s ability to extinguish

the dopamine reward signal at the NA (84, 85), chronic

hyperinsulinemia fosters a sense of starvation and need

for reward, leading to increased caloric intake (86). Lastly,

fructose has been shown to decrease the production in

hypothalamic neurons of malonyl-CoA, which may help

promote a sense of energy inadequacy (87). Together with

promoting hepatic and muscle insulin resistance, fructose

ingestion may alter the hedonic response to food to drive

excessive energy intake, setting up a positive feedback

cycle of hepatic and CNS dysfunction, leading to persistent

overconsumption. Whether this CNS “vicious cycle”

is tantamount to true addiction or merely psychological

dependence is not yet clear. What is clear is that obesity,

depression, and sugar craving and consumption are linked

epidemiologically and mechanistically (88).

SUMMARY

The hepatic metabolic pathways outlined above demonstrate

that fructose is a dose-dependent chronic hepatotoxin.

Fructose is capable of promoting hepatic and

skeletal muscle insulin resistance, hyperinsulinemia,

dyslipidemia, hepatic lipid deposition, and infl ammation;

similar to the dose-dependent toxic effects of ethanol.

Furthermore, the central pathways outlined above demonstrate

that fructose is capable of promoting hypothalamic

leptin resistance and activation of the reward pathway, resulting

in an abnormal drive to continuous consumption,

also similar to ethanol. Indeed, fructose may be described

as “alcohol without the ‘buzz’”.

The metabolic and central similarities between fructose

and ethanol are striking. Other stimulators of the nucleus

accumbens have led to disease and societal deterioration,

and thus have required education, regulation, and in some

instances, interdiction. America attempted ethanol interdiction

(prohibition) in the 1930’s, but was unsuccessful; it

will be even harder to restrict fructose consumption. Furthermore,

the Food and Drug Administration has given

fructose GRAS (generally regarded as safe) status, thus

declining to regulate its use. While many obesity programs

counsel voluntary reductions in personal fructose

consumption, recidivism is frequent; thus, a major effort

in public health education seems daunting. Nonetheless,

we have made signifi cant progress with ethanol reduction,

mostly through regulation. Soda taxes have recently

been proposed both in New York and California, and legislation

for the removal of soft drinks from schools has

been enacted in several states. However, until Yudkin’s

prophecies of 1972 are taken seriously and the public is

made aware of the specifi c dangers of the fructose fraction

of our current Western diet, our current vicious cycle

of consumption and disease will continue.

ACKNOWLEDGMENTS

The author would like to thank Jean-Marc Schwarz,

Ph.D., for his insight and assistance in vetting all the carbohydrate

pathways and biochemistry elaborated in this

article, and Andrea Garber, Ph.D., R.D., Kristine Madsen,

M.D., Patrika Tsai, M.D., M.P.H., Michele Mietus-

Snyder, M.D., and Jung Sub Lim, M.D., Ph.D. for useful

discussions and clinical excellence. ?

About the Author

Robert H. Lustig, MD is Professor of Pediatrics in the

Division of Endocrinology at University of California,

San Francisco. He is a neuroendocrinologist, with specifi

c interests in the central regulation of energy balance.

He is interested in the interactions between leptin

and insulin and how these two hormones are perturbed

to drive weight gain. He is a member of the Endocrine

Society Obesity Task Force and other advisory groups.

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About the Author (Patient Handout – page 38)

Dr. Harry Lefebre’s personal interest in weight control

began as an overweight child. He has nurtured his interest

throughout his entire medical career. He was a

Family Physician for 10 years and his medical practice

began focusing entirely on Bariatrics in 1985. Dr.

Lefebre is Board Certifi ed in Bariatrics and has been an

ASBP member since 1983.